A growing consensus among scientists is that common disorders such as asthma, atherosclerosis, colon cancer, and Alzheimer's disease are all caused in part by a chronic inflammatory syndrome. Generally, chronic inflammation is involved in diseases as diverse as allergy, anemia, aortic valve stenosis, arthritis, atherosclerosis, cancer, heart valve dysfunction, obesity, congestive heart failure, digestive system diseases, and Alzheimer's disease (Brouqui et al. 1994; Devaux et al. 1997; De Keyser et al. 1998). Chronic inflammation inevitably causes tissue damage and is accompanied by simultaneous attempts at healing and repair. The exact nature, extent and time course of chronic inflammation is variable, and depends on a balance between the causative agent and the attempts of the body to remove it. Disorders associated with inflammation are debilitating to individuals suffering from them and cost billions in reduced productivity and increased medical expenses.
Asthma is one of the most common chronic health conditions and is on the rise due to irritants such as pollution and chronic exposure to indoor allergens such as cigarette smoke, cockroaches, dust mites, mold, animals, pollen, cold air, exercise, stress, and respiratory infections. Asthma and related respiratory disorders such as chronic obstructive pulmonary disease (COPD) are chronic or recurring inflammatory conditions in which the airway develops increased responsiveness to various stimuli, characterized by bronchial hyper-responsiveness, inflammation, increased mucus production, and intermittent airway obstruction.
Many inflammatory disorders are mediated by certain cytokines. These include the IL-6 and IL-8 families. Regulation of these and other related cytokines can be a strategy when overstimulation of the immune responses leads to adverse events.
Cytokines are produced predominantly by activated immune cells such as microglia and are involved in the amplification of inflammatory reactions. These include IL-1, IL-6, TNF-α, and TGF-β.
Anti-Inflammatory Compounds
Derivatives of probucol have been developed as therapeutics, for example, for the treatment of cardiovascular disease and as anti-inflammatory agents. Probucol contains two hydroxyl groups and can be modified to form mono-substituted or di-substituted derivatives. Mono-esters and ethers of probucol have been reported to be useful in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, and dermatitis. Methods for treating transplant rejection using mono-substituted derivatives of probucol also have been reported. See U.S. Pat. No. 6,670,398.
U.S. Pat. No. 5,262,439 to Parthasarathy discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups that increase the water solubility of the compound. A series of French patents disclose that certain probucol derivatives are hypocholesterolemic and hypolipemic agents: FR 2168137 (bis 4hydroxyphenylthioalkane esters); FR 2140771 (tetralinyl phenoxy alkanoic esters of probucol); FR 2140769 (benzofuryloxyalkanoic acid derivatives of probucol); FR 2134810 (bis-(3-alkyl-5-t-alkyl-4-thiazole-5-carboxy)phenylthio)alkanes; FR 2133024 (bis-(4 nicotinoyloxyphenylthio)-propanes; and FR 2130975 (bis(4-phenoxyalkanoyloxy)phenylthio)alkanes).
European Patent No. 0348203 to Shionogi Seiyaku Kabushiki Kaisha discloses phenolic thioethers which inhibit the denaturation of LDL and the incorporation of LDL by macrophages. Hydroxamic acid derivatives of these compounds are disclosed in European Patent No. 0405788 and are alleged as useful for the treatment of arteriosclerosis, ulcer, inflammation and allergy. Carbamoyl and cyano derivatives of the phenolic thioethers are disclosed in U.S. Pat. No. 4,954,514 to Kita, et al.
U.S. Pat. No. 6,121,319, and corresponding WO 98/51662 and U.S. Pat. No. 6,147,250 filed by AtheroGenics, Inc., describe certain probucol derivatives and their use for the treatment of disorders mediated including inflammatory and cardiovascular disorders.
WO 01/70757 (also U.S. Pat. No. 6,852,878) filed by AtheroGenics, Inc. describes the use of certain thioethers of the following formula, and pharmaceutically acceptable salts thereof:
whereinRa, Rb, Rc, and Rd are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) C1-10 alkyl or substituted C1-10 alkyl, terminated by sulfonic acid, (iv) C1-10alkyl or substituted C1-10 alkyl, terminated by phosphonic acid, (v) substituted or unsubstituted C1-10 alkyl-O—C(O)—C1-10 alkyl, (vi) straight chained polyhydroxylated C3-10 alkyl; (vii) —(CR2)1-6—COOH, wherein R is independently hydrogen, halo, amino, or hydroxy, and wherein at least one of the R substituents is not hydrogen; or (viii) —(CR2)1-6—X, wherein X is aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.
Meng et al. disclose a series of phenolic inhibitors of TNF-inducible expression of VCAM-1 with concurrent antioxidant and lipid-modulating properties. The compounds disclosed have demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia. (Novel Phenolic Antioxidants As Multifunctional Inhibitors Of Inducible VCAM-1 Expression For Use In Atherosclerosis, Bioorganic & Med Chem. Ltrs. 12(18), 2545-2548, 2002).
WO 05/030721 to Nippon Chemiphar Co., Ltd. describes certain piperidine derivatives as antioxidants. These compound are of the formula:
wherein R1 represents an alkyl group having 1-8 carbon atoms or the like; R2 represents a hydrogen atom, an alkyl group having 1-8 carbon atoms, an alkylcarbonyl group having 2-8 carbon atoms or the like; and R3 and R4 may be the same or different and represent alkyl groups having 1-8 carbon atoms or the like.
WO 91/01124 and related U.S. Pat. No. 5,981,603 and U.S. Pat. No. 5,874,478 to Biodor U.S. Holding and Vyrex Corp. also describes certain compounds for use as antioxidants for treatment of viral infections. These compounds are of the general formula:
wherein n=1, 2, 3, or 4, wherein m=0 or 1, wherein X represents O, S or CH2, wherein R1 represents hydrogen or tertiary butyl or lower alkyl of from one to six carbon atoms, inclusive, R2 represents tertiary butyl or lower alkyl of from one to six carbon atoms, inclusive, and wherein R3 represents hydrogen or alkyl or aryl or mixed alkyl/aryl, containing a total of 5 to 25 carbon atoms. One of the compounds identified in the application is of the following structure:

PCT Publication No. WO 04/037817 to Mitsubishi Pharma Corp. describes certain N-oxide compounds of the formula 1:

U.S. Pat. No. 6,121,272 to the Proctor & Gamble Company discloses certain compounds which are described as inhibitors of metalloproteases. These compounds are of the general formula I:
wherein n is an integer from 1 to 3, and 0 to 2 additional heteroatoms, chosen from O, N, or S, may occur in the backbone of the ring in the place of carbon, and where S occurs it may be in the form S, SO, or SO2 and where N occurs it is in the form NR5 and R5 is chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R10, COR11, CSR12, PO(R13)2; Z is independently one or more of (CH2)m(CR1R2)oSR3; Y is independently one or more of hydrogen, hydroxy, oxo, a spiro moiety, SOR6, SO2R10, alkoxy, aryloxy, alkyl aryl, heteroaryl, COR22CSR12, amino; and Ar is substituted or unsubstituted; alkyl, aryl, carbocyclyl, heterocyclyl, or heteroaryl.
There remains a need for improved compounds and methods for the treatment of chronic inflammatory disorders. In particular there is a need for improved treatments for chronic respiratory inflammatory disorders such as asthma.
It is therefore an object of the present invention to provide new compounds, pharmaceutical compositions and methods for the treatment of inflammatory disorders.
It is a further object of the invention to provide compounds, compositions and methods of treating disorders and diseases mediated by inflammatory cytokines, including respiratory and cardiovascular inflammatory diseases.